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Optogenetic modulation of cardiac vagal function improves prognosis in diabetes

Award Number: R21HL163509
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Optogenetic modulation of cardiac vagal function improves prognosis in diabetes - Project Summary Vagal nerve stimulation (VNS) has emerged as a promising therapy for cardiac arrhythmia by electrical stimulation of vagal nerve at the cervical level. Direct VNS achieves its antiarrhythmic effects through increasing efferent parasympathetic input to the heart. However, patients receiving VNS have reported severe side effects, which are due to off-target stimulation of non-cardiac vagal branches. Cholinergic activation using pharmacological approaches also resulted in serious adverse events due to lack of organ specificity. Increasing vagal efferent input to the heart by targeting cardiac vagal postganglionic (CVP) neurons alone would be ideal to minimize the off-target effects and to achieve precision of parasympathetic activation for anti-arrhythmia. Here, we will introduce a miniaturized bio-optoelectronic implant that avoids limitations of VNS and pharmacological approaches by using optogenetics to treat fatal ventricular arrhythmias in type 2 diabetes mellitus (T2DM). Comparing with electrical and pharmacological approaches, optogenetics provides higher speed and accuracy in regulation of living cell function with less complications. However, a strategy of optogenetic therapy on ventricular arrhythmias in T2DM has not yet been established. Withdrawal of cardiac vagal activity is associated with ventricular arrhythmias-related sudden cardiac death and with high mortality in T2DM patients. Patients with T2DM are two to four times more likely to die from myocardial infarction (MI), compared with non-diabetic patients. Our recent study confirmed that reduction of cell excitability in CVP neurons exacerbates MI-evoked ventricular arrhythmias and mortality in T2DM animals. Considering the advantages of optogenetics including rapid, specific control of neuronal activities by light-sensitive opsins, adeno-associated virus-channelrhodopsin- 2 (AAV-ChAT-ChR2-mcherry) will be transfected into CVP neurons in T2DM animals. Specificity of neuronal expression of ChR2 (an excitatory light-sensitive opsin) in CVP neurons will be achieved by linking the choline acetyltransferase (ChAT, a specific marker of cholinergic neurons) promoter to the ChR2 gene. Continual optogenetic stimulation in CVP neurons will be achieved by illuminating a light-emitting-diodes (LED) probe that is controlled and powered wirelessly in freely moving animals. We hypothesize that optogenetic therapy could restore cell excitability of CVP neurons and acetylcholine (ACh) release from cardiac vagal nerve terminals, further improve vagal control of ventricular function and reduce acute MI-evoked ventricular arrhythmias and high mortality in T2DM. To test this hypothesis, we will determine if optogenetic restoration in CVP neuronal excitability restores ACh release from cardiac vagal nerve terminals, improves vagal control of ventricular function, and reduces MI-evoked fatal ventricular arrhythmias and high mortality in T2DM animals. This proposal will establish the first evidence of the optogenetic therapy on MI-evoked ventricular arrhythmias and mortality in T2DM, and may provide a new therapeutic strategy for improving outcomes and quality of life in T2DM patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $195,000 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	001	2	4/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$195,000
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	003	2	6/28/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$230,250
2024	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cardiovascular Diseases Research	000	1	4/22/2024	NEW	$0
2024	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cardiovascular Diseases Research	002	1	6/28/2024	NEW	-$230,250
														Subtotal = $195,000

Issue Date FY: 2023 ( Subtotal = $230,250 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cardiovascular Diseases Research	000	1	1/30/2023	NEW	$230,250
														Subtotal = $230,250

Grand Total All Awards = $425,250

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Optogenetic modulation of cardiac vagal function improves prognosis in diabetes

Award Number: R21HL163509

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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